From the Guidelines
There is no absolute contraindication to giving dapagliflozin and pioglitazone together, but their combination should be used with caution, particularly in patients with heart failure or those at risk for volume depletion, as evidenced by the most recent study in 2025 1. These medications can be used in combination for patients with type 2 diabetes who need additional glycemic control. Dapagliflozin is an SGLT-2 inhibitor that works by increasing glucose excretion through the kidneys, while pioglitazone is a thiazolidinedione that improves insulin sensitivity in peripheral tissues. Their complementary mechanisms of action can provide additive benefits for blood glucose control. However, patients should be monitored for potential side effects, including:
- Fluid retention and edema (more common with pioglitazone), which could theoretically be exacerbated when combined with the diuretic effect of dapagliflozin.
- Urinary tract infections, genital mycotic infections, and volume depletion associated with dapagliflozin.
- Pioglitazone should be used cautiously in patients with heart failure, as noted in the 2003 consensus statement from the American Heart Association and American Diabetes Association 1. Renal function should be assessed before starting dapagliflozin and periodically during treatment, as it is not recommended for patients with severely impaired kidney function, according to the 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes 1. The combination of dapagliflozin and pioglitazone may also increase the risk of diabetic ketoacidosis, particularly in patients with type 1 diabetes or those with a history of ketoacidosis, as warned by the U.S. Food and Drug Administration in 2015 and discussed in the 2020 standards of medical care in diabetes 1. Therefore, careful consideration of the benefits and risks, as well as close monitoring of patients, is necessary when using this combination therapy, as recommended in the 2017 and 2025 standards of medical care in diabetes 1.
From the FDA Drug Label
A total of 420 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10. 5%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with pioglitazone [a thiazolidinedione (TZD)] alone (NCT00683878) Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of dapagliflozin or placebo in addition to their current dose of pioglitazone.
There is no contraindication to give dapagliflozin and pioglitazone, as the drug label describes a clinical trial where dapagliflozin was used in combination with pioglitazone, indicating that this combination is not contraindicated 2.
From the Research
Contraindications for Dapagliflozin and Pioglitazone
- There is no direct evidence in the provided studies that suggests a contraindication to giving dapagliflozin and pioglitazone together 3, 4, 5, 6, 7.
- Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor indicated for the treatment of type 2 diabetes, and it can be used as monotherapy or in combination with other glucose-lowering agents, including insulin 3.
- Pioglitazone is a thiazolidinedione that can retard the atherosclerotic process and reduce cardiovascular events in patients with type 2 diabetes 5.
- The combination of different glucose-lowering therapies, such as SGLT2 inhibitors and GLP-1 receptor agonists, may improve long-term outcomes for patients with type 2 diabetes by addressing multiple facets of the disease 7.
- However, the safety and efficacy of combining dapagliflozin and pioglitazone specifically are not directly addressed in the provided studies, and therefore, caution should be exercised when considering this combination 3, 4, 5, 6, 7.
Potential Interactions and Considerations
- Dapagliflozin and pioglitazone have different mechanisms of action, and their combination may have complementary effects on glycemic control and cardiovascular risk factors 3, 5, 7.
- However, the combination of these two drugs may also increase the risk of adverse effects, such as hypoglycemia, weight gain, and fluid retention 3, 5.
- Patients with type 2 diabetes who are considering combination therapy with dapagliflozin and pioglitazone should be closely monitored for potential interactions and adverse effects 3, 4, 5, 6, 7.
Glycemic Control and Cardiovascular Benefits
- Dapagliflozin has been shown to reduce the rate of cardiovascular death or hospitalization for heart failure and possibly reduce progression of renal disease in patients with established atherosclerotic cardiovascular disease or multiple risk factors for cardiovascular disease 3, 4.
- Pioglitazone has been shown to reduce cardiovascular events in large randomized prospective cardiovascular outcome trials 5.
- The combination of dapagliflozin and pioglitazone may have complementary effects on glycemic control and cardiovascular risk factors, but further studies are needed to confirm this 3, 4, 5, 6, 7.